Biomedical subjects
Publications and source records attributed to D R Glover.
Many early drug candidates derived from biotechnology failed in clinical trials because of their low affinity/specificity, short half-lives or immunogenicity. Protein engineering techniques have been applied to circumvent some of the problems that hindered these earlier trials, resulting in clinical benefits from a range of engineered antibodies and other proteins.
The efficacy, tolerability and safety of dilevalol in essential hypertension has been documented in an international clinical trials programme which was conducted with doses up to 1600mg daily. Initial double-blind trials confirmed the superiority of dilevalol over placebo in essential hypertensive patients and documented the suitability of a once-daily dosage. Almost all of the subsequent trials have been randomised, double-blind comparative trials of dilevalol versus established anti-hypertensive agents with the duration of treatment ranging from four weeks up to one year. The recommended dosage range of dilevalol, of 200-400 mg once-daily, has generally been shown to be at least as effective at lowering raised blood pressure as established antihypertensive agents given according to their recommended doses. In one study in elderly hypertensives, dilevalol was significantly more effective than atenolol in lowering systolic blood pressure. Safety data is available from a consolidated database of 2011 dilevalol-treated patients representing over 500 patient-years exposure. Overall, dilevalol was well tolerated and evidence of dose-related adverse effects became apparent only for nausea and dizziness above the recommended dose range. The most common adverse effects considered probably or definitely related to treatment were fatigue (2.5%), nausea (1.9%), headache (1.8%) and dizziness (1.7%). 'Typical' beta-blocker adverse effects were observed, though many of these effects were less frequent than seen with comparator beta-blockers. Evidence of excessive vasodilation was rarely found, consistent with the counter-balancing effect of beta-blockade.(ABSTRACT TRUNCATED AT 250 WORDS)
Eighteen male patients (aged 40-66 years) with confirmed ischaemic heart disease and a minimum of four angina attacks per week were included in a double-blind comparison of dilevalol 200 mg, dilevalol 400 mg and atenolol 100 mg. Following a one-week placebo run-in period patients were randomly allocated to one of the three treatments, after which they crossed to the remaining two treatments according to a balanced Latin square design. Each treatment was given once-daily over four weeks. Symptom-limited treadmill exercise testing using a modified Bruce protocol was performed at the end of placebo, and after each treatment around 24 hours post-dosing. The mean exercise time on placebo was 7.0 (+/- 0.91) minutes which changed to 7.8 (+/- 0.93) minutes on dilevalol 200 mg, 7.3 (+/- 0.88) minutes on dilevalol 400 mg and 8.2 minutes (+/- 1.06) on atenolol 100 mg. Nine patients had a greater exercise tolerance on dilevalol (200 or 400 mg), and nine a greater exercise tolerance on atenolol. Maximum exercise heart rate on placebo was 113 (+/- 5.0) beats per minute (bpm) which was reduced to 101 (+/- 3.6), 96 (+/- 2.7) and 98 (+/- 4.9) bpm. on dilevalol 200 mg, dilevalol 400 mg and atenolol 100 mg, respectively. Correspondingly, the rate-pressure product was reduced from 18.1 (x 10(3)) units on placebo to 14.8, 13.4 and 14.4 (x 10(3)) units on each treatment. Pairwise comparisons by the least square mean procedure showed no significant differences between treatments for any of the measured parameters. All treatments caused a reduction in both angina attack rates and trinitrate consumption.(ABSTRACT TRUNCATED AT 250 WORDS)
Although headache is sometimes regarded as a symptom of severe hypertension, its relationship to blood pressure is not clear. In 11,710 patients with mild to moderate essential hypertension we have found that headache was common and may be reduced by treatment. We found a clear relationship between the frequency of reports of headache and both systolic and diastolic blood pressure irrespective of treatment or the type of drug used to treat hypertension. Calcium antagonists appeared most likely to be a cause of headache in hypertensive patients.
1. Lisinopril and enalapril were administered as 2.5 mg single doses and as eight single daily 2.5 mg doses to separate groups of six patients with chronic renal failure. Patients were receiving regular haemodialysis. 2. In the absence of haemodialysis, the decline in plasma concentrations of lisinopril and enalaprilat was extremely slow and plasma concentrations were generally high. 3. Haemodialysis had large effects on plasma concentrations of lisinopril and enalaprilat. A 4 h period reduced plasma concentrations of both drugs by around one-half and often by significantly more than this. Even 1 or 2 h of haemodialysis had significant effects. 4. Haemodialysis plasma clearance was similar for both drugs with mean values of the order of 40 ml min-1. Clearance did not markedly differ when measured after 1, 2 or 4 h of haemodialysis or after single or multiple doses of lisinopril or enalapril. 5. The design of dosage regimens of both lisinopril and enalapril for patients with severe renal impairment or chronic renal failure should take into consideration the use and effects of haemodialysis.
We have evaluated the effect of withdrawal of antihypertensive drugs on the frequency of symptoms over a 2-week period in 11,710 hypertensive patients. Previously untreated patients complained most frequently of headache, dizziness and chest pain, whereas most other symptoms occurred more often in previously treated patients. With the exception of headache, which rose in frequency, most symptoms showed a significant reduction following therapy withdrawal. The burden of symptoms reported by treated hypertensive patients is probably the result of a combination of their disease, drug-related adverse effects and inappropriate use of drugs in certain patient groups.
Beta agonist therapy for heart failure has been disappointing, perhaps because of renin induced aldosteronism. To investigate this possibility we measured plasma renin activity (PRA) in 23 patients (17 male, 6 female, age 41-70) with New York Heart Association stage III heart failure due to ischaemic heart disease in a placebo controlled trial over one month. All patients received constant doses of digoxin and diuretics throughout the trial. Compliance was confirmed in all patients by digoxin and prenalterol assay. In a preliminary (dose titration) study of 9 patients there was a progressive, but non-significant rise of mean PRA from 14.8 to 17.6 and 27.7 ng/ml per h with doses of 20, 50 and 100 mg of prenalterol, respectively. After one month of treatment with prenalterol (n = 11), PRA was 12.8 +/- 2.4 (SEM) ng/ml per h which was not significantly different from the initial level of 14.4 +/- 2.3 ng/ml per h (n.s.). The placebo group (n = 12) results were 13.8 +/- 4.2 ng/ml per h at entry and 14.4 +/- 5.2 ng/ml per h at one month (n.s.). These results indicate that PRA is elevated by acute treatment with the partial beta agonist prenalterol but stimulation of renin secretion does not appear to occur with chronic therapy.
An evaluation of factors which may influence survival and mode of death was conducted over a three year period in a consecutive series of 50 patients with severe chronic ischaemic cardiac failure for more than three months. At the initial assessment all patients were already receiving intensive medical treatment. During follow up four patients successfully underwent cardiac surgery and medical treatment was modified in most patients, with four patients receiving antiarrhythmic drugs. Twenty six patients died: 17 suddenly within one hour of onset of symptoms and nine of progressive cardiac failure. The mortality by one year was 26% and by two years it was 62%. Comparison of those who survived with those who died within one year of follow up showed that a very low left ventricular ejection fraction, severe ventricular arrhythmias, the presence of gallop rhythm, and New York Heart Association class IV were the variables that predicted mortality. By two years left ventricular ejection fraction, ventricular arrhythmias, and pulmonary capillary wedge pressure were the variables that were significantly different in survivors and patients who died. No differences were found in any of the recorded variables between those who died suddenly and those who did not. Thus in patients with chronic ischaemic cardiac failure determination of the left ventricular ejection fraction and the severity of ventricular arrhythmia on the ambulatory electrocardiogram are the best ways to predict prognosis. The presence of gallop rhythm and New York Heart Association class IV status predict early death.
Lisinopril is a new, long-acting, nonsulfhydryl angiotension-converting enzyme (ACE) inhibitor that is excreted unchanged by the kidney. The antihypertensive efficacy and safety profiles of lisinopril were assessed in 24 patients (15 men, 9 women; mean age 52.3 years; range 21-75 years) with hypertension associated with impaired renal function (glomerular filtration rate GFR 60 ml/min or less), in an open study of 12 weeks' duration. Previous antihypertensive drugs were discontinued at entry into the study. Lisinopril was given orally once daily; the starting dose was 2.5 mg in patients with a GFR of less than 30 ml/min, and 5 mg in all other patients. The dosage of lisinopril was titrated upward to 40 mg daily according to BP response. A diuretic could then be added if hypertension was inadequately controlled. Twenty-three patients completed the study. Mean sitting BP was reduced from 177 +/- 21.2/106 +/- 9.1 mm Hg (mean +/- SD) at entry to the study to 145 +/- 21.4/88 +/- 8.3 mm Hg after 12 weeks of treatment (p less than 0.001). The median dose of lisinopril used was 10 mg (range 2.5-40 mg) and only 4 patients had a diuretic added to the lisinopril. Overall GFR was unchanged during the study: mean baseline value was 37 +/- 16.4 ml/min (range 10-60 ml/min) at the beginning of the study and 40 +/- 21.0 ml/min at the end. As in a previous pharmacokinetic study in similar patients, a tendency toward drug accumulation was noted only in those patients with the most severe renal impairment.(ABSTRACT TRUNCATED AT 250 WORDS)
Based on prevailing hypotheses about the role of renin in essential hypertension, both Laragh and Buhler independently predicted that angiotensin-converting enzyme (ACE) inhibitors would become less effective with increasing age, as elderly hypertensive patients tend to have low plasma renin activity. We have investigated this situation in a large postmarketing surveillance study with enalapril. Following a 2-week no-treatment period, a total of 11,710 patients with essential hypertension received 10-20 mg of enalapril once daily for 6 weeks. BP was measured on two occasions prior to enalapril treatment, and on two occasions during enalapril treatment (after 2 and 6 weeks). Enquiry for symptom events was also made on each of these four occasions. Systolic BP (SBP) prior to enalapril treatment rose steeply with increasing age, whereas diastolic BP (DBP) rose only very slightly with age and reached a plateau by the 5th decade. The fall in SBP in response to enalapril increased with increasing age, but DBP was relatively uninfluenced by age. However, when corrected for initial BP, the percentage changes in both SBP (13%) and DBP (14%) were not different across the age range studied. Prior to receiving enalapril, 67.8% of patients were reporting symptoms, and this showed a positive correlation with age. During enalapril therapy, the overall level of symptom events reported fell significantly in all age groups (35.0%) but more so in the elderly, such that at the end of the study no significant age-related difference was detected. In all age groups, more than half of the events reported during enalapril therapy were of an improvement in general well-being.(ABSTRACT TRUNCATED AT 250 WORDS)
The efficacy and biochemical effects of two low-dose thiazide plus potassium-sparing diuretic preparations were compared in the treatment of elderly patients with stable, mild to moderate congestive heart failure. Sixty patients (mean age 80 years) were randomly allocated to treatment with 1 tablet daily of either 25 mg hydrochlorothiazide/2.5 mg amiloride or 25 mg hydrochlorothiazide/50 mg triamterene. The dose was increased to 2 tablets daily if necessary, after 2 weeks, for a further 6 weeks. Patients' response to treatment was assessed at 2, 4 and 8 weeks using a simple clinical scoring system for signs and symptoms of their condition, and routine biochemical analysis was carried out at baseline and the end of treatment. One patient was withdrawn from the study due to a rash which was probably related to hydrochlorothiazide/amiloride treatment. A further 11 patients were excluded from the analysis because of intercurrent illness or inadequate records. Analysis of the results from 48 patients showed that both treatments resulted in an improvement in clinical score and weight reduction, with more than three-quarters of the patients responding to treatment. No serious biochemical disturbances occurred; in particular, no new cases of hyponatraemia (serum sodium less than 130 mmol/l) developed. Both preparations, therefore, were effective and tolerated forms of treatment for mild to moderate congestive heart failure in the elderly and there were no significant differences between them.
We examined the effect of three antihypertensive agents with differing modes of action on blood pressure, heart rate, plasma catecholamines, plasma renin activity, and echocardiographic left ventricular mass. Twenty-six patients were studied; nine were treated with nifedipine, a calcium antagonist, nine were treated with timolol, a nonselective beta-blocker, and eight were treated with indapamide, a diuretic with some probable calcium antagonist properties. All drugs reduced blood pressure satisfactorily; the reduction of systolic blood pressure was not significantly different among the three drugs, but timolol reduced diastolic blood pressure by a greater amount than did either indapamide or nifedipine. Left ventricular (LV) mass was reduced equally by all three drugs. However, there were markedly different effects on the other parameters measured. Heart rate was reduced to a greater extent by timolol than by the other two drugs. Plasma renin activity was reduced by timolol, unchanged by nifedipine, and increased by indapamide. There were no significant changes in either adrenaline or noradrenaline with any of the three drugs. We conclude that these data do not support the hypothesis that the sympathetic nervous system is primarily responsible for left ventricular hypertrophy, and suggest that reduction of left ventricular mass with antihypertensive agents is not the property of any one class of drug.
The clinical effects of the oral beta 1 partial agonist, prenalterol, were investigated in 37 patients (29 male, eight female; mean age 57 years) with chronic ischaemic left ventricular failure using a placebo controlled randomised double blind protocol over six months. All patients were limited by dyspnoea (New York Heart Association class III) despite treatment with digoxin and diuretics. Twenty eight patients completed the protocol. Moderate clinical improvement was seen in the prenalterol group, whereas there was little change in the placebo group. Bicycle exercise capacity increased over six months in the prenalterol and placebo groups but only achieved statistical significance for prenalterol when compared with baseline values. Maximum exercise heart rate was significantly reduced in the prenalterol group compared with placebo. Radionuclide left ventricular ejection fraction at rest and during exercise and cardiothoracic ratio showed no significant improvement in either group over six months. Prenalterol was well tolerated and produced no increase in frequency of angina or ventricular arrhythmias. Prenalterol produced clinical benefits and improved exercise tolerance while reducing exercise heart rate. A moderate placebo response was noted. The apparent beta blocking effect of prenalterol may be as important as the beta 1 agonist effect in producing these benefits. Prenalterol has, however, been withdrawn because of side effects in animals.
Nine elderly and 11 young hypertensives underwent continuous ambulatory monitoring of blood pressure (BP), assessment of cardiovascular reflexes and M-mode echocardiography as hospital in-patients prior to treatment with once-daily indapamide (2.5 mg). They were followed as out-patients for 4 months during which time casual BP was measured at monthly intervals. The patients were then readmitted to hospital and studied using the same protocol under similar standardised conditions. The results showed that indapamide reduced casual and ambulatory BP in both young and elderly although the most marked effect was seen on systolic BP. Assessment of cardiovascular reflexes indicates that at least part of the hypotensive action of indapamide is due to a diuretic effect. Treatment with indapamide has comparable results on both young and elderly.
Patients surviving 2 weeks after myocardial infarction who had persistent conduction disorder (right bundle branch block alone or associated with left anterior or posterior hemiblock [LPH] or LPH alone) were allocated at random to permanent pacing or control groups. Throughout follow-up, up to 5 years, there was no significant difference in survival: at 2 years 14 of 23 (61%) of paced patients had died compared with 11 of 27 (41%) control patients. Progression of conduction disorder was not observed and measurement of infranodal conduction time (HV interval) did not predict outcome. Ventricular tachyarrhythmias were an important cause of death in these patients and pacing appears to offer no benefit.
Since 1979 we have carried out symptom limited exercise stress tests for the diagnosis of chest pain in 104 patients, 61 male, 43 female, over 65 years of age; mean age 68 +/- 3 years. An upright bicycle ergometer was used for 64 tests, a treadmill for 38 tests and a supervised walk for 2 patients unable to undergo formal exercise testing. A positive result of greater than or equal to 1 mm of ST depression was recorded in 45% of patients; males 57%, females 28% (P less than 0.01). Bicycle and treadmill tests were equally likely to produce a positive result; bicycle 43%, treadmill 50% (NS). The limiting symptom was chest pain in 43%, dyspnoea in 26% and fatigue in 30% of patients. No serious arrhythmias or collapses occurred. During a mean follow up to 24 +/- 18 months 13 patients died. A positive exercise test was associated with a significantly increased risk of cardiac death; 8 of 47 patients with positive tests died compared with 1 of 57 patients with negative or equivocal tests (P less than 0.02). The remaining 4 deaths were due to malignancy. Exercise testing can thus be safely performed in elderly subjects with the expectation of a high diagnostic yield. A positive result confers a poor prognosis.
The severity and pattern of coronary artery disease in patients referred for investigation of the disease was compared between Asian and white patients living in Birmingham, matched for age, sex, blood pressure, and duration of symptoms, to investigate the clinical impression that Asians have worse, in particular worse distal, coronary artery disease than whites. Risk factors and outcome were also examined. The coronary angiograms of 34 Asians were compared blindly and repeatedly with those of 68 whites by two independent observers. Coronary artery disease was found to be quantitatively more severe in Asians, but the distribution of the disease was the same. Some risk factors were significantly different: fewer Asians were smokers; fasting cholesterol concentrations were higher in whites; and whites were heavier, with a larger body surface area. Follow up data showed that more Asians were refused coronary artery bypass surgery because of the severity of their disease.
Thirty-four Asian patients with coronary artery disease (CAD) were each matched for age, sex, blood pressure and duration of symptoms with 2 white patients with CAD. Blind assessment of coronary arteriograms demonstrated significantly more severe disease in Asians but distribution of disease was similar in both groups. Assessment of risk factors showed that the Asian group had significantly more non-smokers, lower cholesterol levels and weighed less than whites.